Cell non-autonomous regulation of proteostasis in aging Summary The contribution of cell autonomous and cell non-autonomous events in aging has only recently been recognized, leading to questions of how metazoans detect and integrate such information to determine overall health. Our studies in C. elegans have provided insights into these events, leading us to propose that proteostasis is regulated at the organismal level by transcellular signals to determine health and longevity. The overall goal of this proposal is to elucidate the signaling network that controls organismal proteostasis in the sending tissues, and characterization of the response in receiving tissues. For this, we will use C. elegans as the discovery tool and extend our observations to human cells. This will be accomplished in three Aims: (1) to use a tissue-targeted genetic screening method that will identify genes and pathways that regulate cell non- autonomous proteostasis during aging, (2) to analyze the consequences of cell non-autonomous signaling on proteostasis function in the receiving tissues, and (3) to demonstrate functional conservation of the cell non- autonomous signaling pathways using patient-derived neurons. These studies will provide new insights into the molecular mechanisms underlying cell non-autonomous communication that regulate proteostasis and aging.